1. Field of the Invention
The present invention relates to a method of treating movement disorders of a living being, a method of treating refractory gait disturbances of a human Parkinson's disease patient being affected by gait disturbances, and an apparatus for deep brain stimulation (DBS) of a living being affected by movement disorders.
2. Related Prior Art
Movement disorders refer to a group of diseases and syndromes affecting the ability to produce and control movement. Examples include akathisia (inability to sit still), akinesia (lack of movement), ataxia (gross lack of coordination of muscle movements), bradykinesia (slow movement), tremor, spasms, gait disturbances etc.
Parkinson's disease (PD) is the most common neurogenerative movement disorder. Severe gait disturbances in idiopathic PD are observed in up to 80% of the patients in advanced disease stages with important impact on quality of life.
Therapeutic deep brain stimulation (DBS) of the subthalamic nucleus (STN) as an evidence-based PD therapy generally ameliorates segmental symptoms and motor fluctuations; cf. Deuschl et al.: A randomized trial of deepbrain stimulation for Parkinson's disease. N Engl J Med 2006, 9:896-908; Kleiner-Fisman et al.: Subthalamic nucleus deep brain stimulation: summary and meta-analysis of outcomes. Mov Disord 2006, 21(Suppl 14):290-304; Weaver et al.: Bilateral deep brain stimulation vs. best medical therapy for patients with advanced Parkinson disease: a randomized controlled trial. Jama 2009, 1:63-73.
However, in PD axial symptoms and in particular gait disturbances may respond unfavorably and generally aggravate in parallel with the underlying neurodegeneration; cf. Krack et al.: Five-year follow-up of bilateral stimulation of the subthalamic nucleus in advanced Parkinson's disease. N Engl J Med 2003, 349:1925-1934; Moore et al.: Freezing of gait affects quality of life of peoples with Parkinson's disease beyond its relationships with mobility and gait. Mov Disord 2007, 22:2192-2195; Moreau et al.: STN-DBS frequency effects on freezing of gait in advanced Parkinson disease. Neurology 2008, 71:80-84. In this condition, increasing intensity of high-frequent STN-DBS at 130 Hz even worsens the condition; cf. Moreau et al., loc cit.
Currently, several approaches are under investigation in order to address the therapeutic need for gait disturbances of PD patients refractory to dopaminergic treatment and STN-DBS. STN-DBS on lower frequencies, e.g. at 60 Hz can improve gait disturbances, however is limited by the recurrence of segmental symptoms like tremor, bradykinesia and rigidity; cf. Moreau et al. loc cit.
Stimulation of the pedunculopontine area for refractory gait disturbances remains controversial at the moment Ferraye et al.: Effects of pedunculopontine nucleus area stimulation on gait disorders in Parkinson's disease. Brain 2010, 133:205-214; Moro et al.: Unilateral pedunculopontine stimulation improves falls in Parkinson's disease. Brain 2010, 133:215-224; Stefani et al.: Bilateral deep brain stimulation of the pedunculopontine and subthalamic nuclei in severe Parkinson's disease. Brain 2007, 130:1596-1607.
Several experimental lines of evidence demonstrated the integrative role of reciprocal brainstem circuitries including substantia nigra pars reticulata (SNr) and the pedunculopontine area; Aziz et al.: The role of descending basal ganglia connections to the brain stem in parkinsonian akinesia. Br J Neurosurg 1998, 12:245-249; Breit et al.: Lesion of the pedunculopontine nucleus reverses hyperactivity of the subthalamic nucleus and substantia nigra pars reticulata in a 6-hydroxydopamine rat model. Eur J Neurosci 2006, 24:2275-2282; Jenkinson et al.: Pedunculopontine nucleus stimulation improves akinesia in a Parkinsonian monkey. Neuroreport 2004, 15:2621-2624.
Importantly, activity of the SNr can be modulated after implantation for conventional STN-DBS, as the caudal electrode contacts are generally located in the caudal border zone of STN and SNr; cf. Chastan et al.: Effects of nigral stimulation on locomotion and postural stability in patients with Parkinson's disease. Brain 2009, 132:172-184;
Recently, a concomitant deep brain stimulation of the substantia nigra pars reticulata additional to the subthalamic nucleus for a time period of 3 to 6 weeks has been suggested to treat gait disturbances in PD; cf. Weiss et al.: Combined stimulation of the substantia nigra pars reticulata and the subthalamic nucleus is effective in hypokinetic gait disturbance in Parkinson's disease. J Neurol 2011, 258:1183-1185; Weiss et al.: Combined STN/SNr-DBS for the treatment of refractory gait disturbances in Parkinson's disease: study protocol for a randomized controlled trial. Trials 2011, 12:222. The contents of both of the before-identified documents of Weiss et al. are herewith incorporated by reference.
However, the inventors have realized that PD patients treated with the approach as disclosed by Weiss et al. develop tolerance after several days of treatment and the gait disturbances recur.
Therefore, there is an unmet need for further symptomatic therapeutic strategies, particularly as gait disturbances generally respond unfavorably to dopaminergic medication and conventional deep brain stimulation of the subthalamic nucleus in advanced disease stages.